The development of safe and efficacious vaccines remains a major goal in global public health.
In particular, vaccines termed “mucosal” have emerged as an attractive potential alternative to injectable vaccines.
Mucosal administration has many potentially desirable attributes. Perhaps the most compelling reason for developing mucosal vaccine delivery techniques is development of a first line of immunity defense, by generating local immunity at the mucosal site of entry for many invading pathogens.
Moreover some investigators have reported that a common mucosal immune system exists, whereby mucosal immunity induced at one site can lead to immunity at a distal mucosal site (McGhee, J. R. et al. The mucosal immune system: from fundamental concepts to vaccine development. Vaccine 1992, 10:75-88).
In addition, delivery of an antigen via a mucosal site has the potential to generate a systemic immune response as well.
This suggests that significant benefits can be achieved by the delivering of vaccines in a non-invasive way, e.g. intranasally or other mucosal route, to elicit immunity to a wide range of pathogens that may enter at different mucosal sites.
The majority of the present day vaccines (mucosal vaccines or other) are composed of two main components: (i) the target antigen of therapeutic interest and (ii) immunoadjuvant compound(s) that stimulate and/or induce immunogenicity against said antigen.
The nature of known immunoadjuvants varies greatly, but includes in particular mineral oils, bacterial extracts, live and attenuated organisms and suspensions of aluminum hydroxide metals.
Even if adjuvants provide enhance immune responses, their use can also elicit adverse side effects, function notably of their administered route. Therefore, the numbers of adjuvants that are approved and effective in humans remain relatively limited.
Advances in the field of innate immunity have provided a better understanding of both the cellular and molecular mechanisms governing the regulation of the host immune response.
This better knowledge of immune system has allowed the research and development of new potential useful immunoadjuvants.
In particular, toll-like receptors (TLRs) are instrumental in the coordinated induction of innate and adaptive immunity in mammals. Since TLRs are expressed by a broad variety of cell types, they are able to trigger immunity throughout the body.
Following infection by pathogenic microorganisms, TLRs recognize conserved motifs referred to as microbe-associated molecular patterns (MAMPs). TLR engagement induces a gene expression program dedicated to both innate clearance of and acquired immunity to pathogenic microorganisms. For instance, TLRs induce the production of chemokines which, in turn, specifically attract the polymorphonuclear neutrophils (PMNs) directly involved in innate microbial clearance. Furthermore, TLRs promote the secretion of pleiotropic immune mediators (such as TNFα) and the functional maturation of dendritic cells (DCs) which specialize in antigen presentation to lymphocytes.
Consequently, TLR agonists not only stimulate “broadly specific” pro-inflammatory immune responses but also enhance the adaptive immune response to defined antigens, and are thus considered to be immunoadjuvants.
Despite these potentially beneficial effects, the systemic toxicity of MAMPs has prompted efforts to develop derivatives that bias MAMP activity towards adjuvancy. Indeed, engineering molecules with unique properties is a major challenge in manipulating immune responses.
Bacterial flagellins (the major flagella components in many bacterial pathogens) are specific, unique agonists for TLR5 activation.
The FliC flagellin from Salmonella enterica Serovar Typhimurium (S. Typhimurium) is the paradigm for studies on flagellum structure-function, immunity and TLR5 signaling.
It is a 494 amino-acid protein with two distinct domains. The amino- and carboxy-terminal “conserved” regions form a domain that is essential for TLR5 activation.
The middle domain of flagellin FliC comprises amino acids not mandatory for TLR5 signaling. It is designated as a “hypervariable” region, since the primary sequences greatly vary in composition and size from one bacterial species to another. In contrast, it is known that the hypervariable region is essential for flagellin antigenicity.
It has been shown that intravenous (i.v.) injection of flagellins promotes a systemic response, characterized by the production of pro-inflammatory mediators (such as TNFα or IL-6) and DC activation.
Furthermore, flagellins trigger mucosa-specific innate and adaptive defense mechanisms. For instance, epithelial cell lines and lung mucosa upregulate the production of chemokines like CXCL8 (IL-8) and CCL20 which, in turn, recruit mucosal PMNs and DCs, respectively.
Various authors have also reported that flagellins are potent systemic and mucosal immunoadjuvants that elicit (i) serum and/or secretory antibody responses and (ii) Th1 and Th2 cell responses to both the flagellins themselves and co-administered antigens.
Due to their potent systemic and mucosal immunoadjuvant activities, flagellins may be particularly interesting for the development of vaccine, and in particular of mucosal vaccine type.
However, most of the said flagellin-type adjuvants are not completely suitable for such vaccine application, and in particular for said mucosal vaccine strategy.
Indeed, the known flagellin adjuvants show major side effects, and in particular intrinsic antigenic activity and systemic pro-inflammatory properties when administered in vivo.
Moreover, most of the known flagellin-type immunoadjuvants need to be physically linked to the target antigen, in order to elicit a potent immune response when administered in vivo. This requirement obliges supplementary complex manipulations to obtain a suitable flagellin-antigen linkage, and the final useful immunogenic substance.
There is thus a need for new compounds which could be used as immunological adjuvants, in particular to induce and/or to enhance mucosal immune response against an antigen, notably without triggering any significant systemic inflammation side effect.
These new compounds should also, advantageously, be able to trigger an immune response by a simple mixture with the target antigen.
The present invention proposes then new immunoadjuvant compounds that satisfy this need, and which can be particularly useful for the production of immunogenic compositions and of vaccine (in particular of mucosal type).